IADR Abstract Archives
Engineering Alpha-Ketoglutarate for Bone Regeneration
Objectives: Alpha-ketoglutarate (AKG), a key Tricarboxylic acid cycle component, has garnered attention for its antiaging properties in various organisms. Our recent study has shown that Dimethyl alpha-ketoglutarate (DMAKG), a cell-permeable derivative of AKG, significantly promotes osteogenic differentiation and bone regeneration. However, its cytotoxicity and rapid hydrolysis limit its application. To address these challenges, new AKG-releasing 3D macro-porous scaffolds for tissue engineering applications have yet to be developed.
Methods: Specifically, we designed and synthesized a novel polyester incorporating an AKG moiety (PAKG) to fabricate nanoparticles (NPs). Preosteoblast MC3T3-E1 cells and mouse bone marrow mesenchymal stem cells (mBMSCs) were cultured with NPs to test the osteoblastic differentiation and mineralization. Furthermore, we developed a macro-porous microparticles (MPs) with PLGA and PAKG as scaffold for cell growth/differentiation and delivery. The in vivo bone regeneration study was conducted using mice with critical-sized cranial bone defect.
Results: Excitingly, these biodegradable PAKG NPs were highly phagocytosable for nonphagocytic cells (e.g., pre-osteoblasts MC3T3-E1 and primary bone marrow MSCs) while common poly (L-lactic acid) and poly (lactic-co-glycolic acid) MPs (PLLA & PLGA) with similar size fail to do so. In vitro studies demonstrated that PAKG NPs significantly promoted osteoblastic/osteogenic differentiation and subsequent mineralization in different cell types. The in vitro data also suggested that the chemical components, hydrophilicity, and the size of the particles significantly affected the cytotoxicity and pro-osteogenic activity. The in vivo studies showed that PAKG-based NPs significantly promote the cranial bone regeneration of mice. Moreover, the osteoblastic/osteogenic differentiation and subsequent mineralization in different cell types were significantly improved by the PLGA-PAKG porous MPs compared to PLGA porous MPs group.
Conclusions: In summary, the novel PAKG and the porous PLGA-PAKG MPs scaffold showed capabilities in osteogenic differentiation and bone regeneration and held great potential for broad regenerative medicine.
Methods: Specifically, we designed and synthesized a novel polyester incorporating an AKG moiety (PAKG) to fabricate nanoparticles (NPs). Preosteoblast MC3T3-E1 cells and mouse bone marrow mesenchymal stem cells (mBMSCs) were cultured with NPs to test the osteoblastic differentiation and mineralization. Furthermore, we developed a macro-porous microparticles (MPs) with PLGA and PAKG as scaffold for cell growth/differentiation and delivery. The in vivo bone regeneration study was conducted using mice with critical-sized cranial bone defect.
Results: Excitingly, these biodegradable PAKG NPs were highly phagocytosable for nonphagocytic cells (e.g., pre-osteoblasts MC3T3-E1 and primary bone marrow MSCs) while common poly (L-lactic acid) and poly (lactic-co-glycolic acid) MPs (PLLA & PLGA) with similar size fail to do so. In vitro studies demonstrated that PAKG NPs significantly promoted osteoblastic/osteogenic differentiation and subsequent mineralization in different cell types. The in vitro data also suggested that the chemical components, hydrophilicity, and the size of the particles significantly affected the cytotoxicity and pro-osteogenic activity. The in vivo studies showed that PAKG-based NPs significantly promote the cranial bone regeneration of mice. Moreover, the osteoblastic/osteogenic differentiation and subsequent mineralization in different cell types were significantly improved by the PLGA-PAKG porous MPs compared to PLGA porous MPs group.
Conclusions: In summary, the novel PAKG and the porous PLGA-PAKG MPs scaffold showed capabilities in osteogenic differentiation and bone regeneration and held great potential for broad regenerative medicine.